Exposure to diesel exhaust (DE) is associated with airway inflammation, increased susceptibility to viral infection, and modification of innate immune responses. Using tightly linked human in vitro and in vivo translational research models, the parent grant investigates a.) the effects of DE on susceptibility to influenza virus in humans in vivo using inoculation with the live-attenuated influenza virus (LAIV) vaccine and b.), the effects of DE on NK cells and T cells during influenza infections. The goal of the consortium is to develop novel technologies and integrated complementary experimental approaches to investigate how exposures to DE modify innate immune responses in humans by testing the hypothesis that exposure to DE prior to infection with influenza increase the release of endogenous ligands, such as hyaluronic acid (HA), which changes NK cell and neutrophil activity, resulting in modified innate immune responses. This ViCTER proposal is divided into 3 interrelated new specific aims (SA), involving investigative teams spanning various schools and departments at UNC, NCSU, and Duke University. SA1 will expand the scope of the parent grant and examine the role endogenous ligands, such as hyaluronic acid (HA) and neutrophils in the modified innate immune responses seen in subjects exposed to DE prior to inoculation with live attenuated influenza virus (LAIV). SA2 will use genetic mouse models and pharmacological interventions to generate mechanistic understanding related to the role of HA as a potential mediator modifying immune function. The human and mouse studies described in SA 1 and 2 are directly linked by a.), using the same DE particles for the human and mouse in vivo exposure studies and b.), focusing on HA as a potential mediator affecting innate immune responses using a novel experimental platform developed by investigators at UNC, the team in SA3 will be using cells obtained from human subjects enrolled in specific aim 1 and develop a single-cell assay to quantify DE-induced effects on lipid signaling. This ViCTER program supports trans-disciplinary research necessary to develop novel translational research tools to investigate mechanisms by which exposure to pollutants affects respiratory innate immune responses.